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Web Guide 2: Program
Supplement: Alan P Venook, MD
DR ALAN VENOOK SUPPLEMENT
DR NEIL LOVE: The
ASCO presentations on both the FOLFOX and capecitabine/oxaliplatin
studies are part of an emerging trend in colorectal cancer towards
more therapeutic options and a gradual improvement in our ability
to control the disease. The primary goal of Colorectal Cancer Update,
like our breast cancer audio series, is to obtain research leader
viewpoints on what this all means to day-to-day patient care. To
learn more about this, I met with Dr Alan Venook and asked him to
select from his practice a patient who typified the current challenges
in the treatment of colorectal cancer. Dr Venook selected a man
with a very unusual initial clinical presentation.
DR ALAN VENOOK: He’s a 45-year-old gentleman,
who presents with about six months of weight loss and abdominal
complaints. Ultimately, he is admitted to the hospital with fevers.
His evaluation shows that he has large liver metastases that, in
fact, look abscessed. And his evaluation reveals that he’s
got a large colon cancer primary with super-infected liver metastases.
DR. LOVE: Wow! And he had,
obviously, no prior history of colorectal cancer.
DR VENOOK: He had no history of colorectal cancer.
Young man, no family history, just sort of out of the blue presents
with liver metastases. And, as is not unusual in young people, he
either denies the symptoms or he’s in good enough condition
before this that the disease is quite advanced before it comes to
attention.
DR. LOVE: Where in the colon
was it?
DR VENOOK: It was in the right colon by the hepatic
flexure. So, his tumor had essentially seeded, bacteria seed from
the tumor, into his metastases. Now, the first course of action
was for him to be treated with antibiotics, which he was. He had
an abscess drained in the liver and was clinically well, but now
has multiple hepatic metastases, a primary tumor in place, and the
question is – How do you manage this patient?
DR. LOVE: Now, just to backtrack
a little bit. So, you’re saying that the primary tumor directly
eroded into the liver?
DR VENOOK: It could have done that, but in this
case the tumor led to bacterial seeding in the bloodstream. It’s
long been known, for example, that colon cancer can cause Strep
bovis endocarditis, because bacteria seed from the bowel into the
bloodstream and then can seed a heart valve. One of the wonders
is that metastases don’t get infected more often than they
do. But in this case, he had his primary tumor and bacterial seeding
of the metastases with an abscess. So, by the time we saw him, he
has been on antibiotics for weeks and has had drainage of one of
the hepatic metastatic abscesses. He’s 45 years old, but is
really still showing the ravages of his illness.
DR. LOVE: That’s an amazing
case. How many cases have you seen before with infected hepatic
metastases?
DR VENOOK: As I said, it’s surprising we
don’t see it more often. We see probably two or three a year.
DR. LOVE: Huh. Wow. Did he
have GI symptoms?
DR VENOOK: Well, in retrospect, he would admit
to some trouble with intermittent diarrhea and constipation, although
he’d never made an issue of it before he got ill. He admits
to being ill for a few weeks before he had the high fevers that
led to his admission.
DR. LOVE: And was he working?
DR VENOOK: He’s a venture capitalist, so
I’m not sure if they work or not, but he was making money
I’m sure.
DR. LOVE: I guess when you
described him, my first thought was that maybe this is somebody
who doesn’t take care of himself.
DR VENOOK: No, this is a fit triathlete who had
been fatigued for a while, so he wasn’t competing.
DR. LOVE: So, it wasn’t
a case of extensive denial or was it? I mean, do you think he knew
he was sick and didn’t want to seek treatment?
DR VENOOK: It’s always hard to tell. He
probably knew he was sick for a while, but surprisingly not as sick
as you might have expected. But by the time we saw him, he’s
now been in the hospital on antibiotics with resolved bacteremia.
So, this is a 45-year-old guy who is not in very good shape.
DR. LOVE: How about his liver
function?
DR VENOOK: His liver function and bilirubin were
normal, but his LVH was 900. His tumor volume – it occupied
at least half of his liver, and his primary tumor was in place.
He’d also had a treated infection, although we had no evidence
of active infection.
DR. LOVE: Any tumor anywhere
else besides the colon and liver?
DR VENOOK: The only site of tumor was in the
liver and in the colon, although the issue that we first faced was
should we do an operation to remove his primary tumor. So, that
was the first question. We felt that his performance status really
was marginal enough, and having just recently been treated for bacteremia,
that we’d like to avoid doing a big operation at that time.
So, we were presented with the question of – How do you treat
this young, but relatively debilitated colon cancer patient? How
do you optimally treat him?
DR. LOVE: How extensive was
the primary tumor?
DR VENOOK: The primary tumor was minimally symptomatic.
It was in the right colon, so it wasn’t nearly obstructed.
It wasn’t bleeding actively. His hemoglobin was 12 grams,
so he was minimally anemic, but not profoundly bleeding.
DR. LOVE: What do you think
the options are for a patient in this kind of situation?
DR VENOOK: Well, the options would be to treat
him aggressively with combination chemotherapy something like irinotecan/5-FU/leucovorin.
At our place, we’re doing a Phase II study looking at irinotecan/5-FU/leucovorin
with an angiogenesis inhibitor. So, could we offer him that? A third
option would be 5-FU/leucovorin alone and a fourth option was Xeloda.
The fifth option was to do an operation first and then regroup after
the operation.
DR. LOVE: The angiogenesis
study, is that randomized?
DR VENOOK: No. That’s a Phase II. At the
time, it was a Phase II study, so all patients were treated with
combination chemotherapy and the angiogenesis inhibitor. The end
point of the study is response rate and safety. The angiogenesis
inhibitor is Angiozyme®, which is a ribozyme to one of the VEGF
receptors.
DR. LOVE: What did you decide
to do with him?
DR VENOOK: Well, the patient wanted to be very
aggressive in his therapy, as did the family. So, on the first visit,
we actually deferred the decision because his performance status
was marginal. The second visit, about two weeks later, he insisted
he was getting around and doing reasonably well and didn’t
appear to have active infection. So, we offered him the aggressive
treatment, and he actually did participate in the research trial,
making the cutoff for performance status barely, but making all
the other criteria. Again, this is a 45-year-old who really had
a vision of being fully aggressive.
DR. LOVE: When did that occurred?
DR VENOOK: This was just in the last three months.
DR. LOVE: Hmm. Wow.
DR VENOOK: So, the patient was treated on the
aggressive therapy and, consistent with what we’ve been learning,
he tolerated it extremely poorly. So, although he was young and
relatively fit, his burden of disease and his ill being wound up
making him unable to tolerate the chemotherapy. Now, he did receive
an experimental agent, but there was no evidence that that experimental
agent contributed to his toxicity.
DR. LOVE: What kind of toxicity
has been seen with that?
DR VENOOK: There have been really no toxicities
that are clearly associated just with the experimental agent. There’s
concern with angiogenesis inhibitors, that they may change or affect
hemostasis and coagulation parameters. This fellow had none of those
problems. His main problem was horrendous fatigue and some diarrhea,
although fatigue was his dominant problem to the point that he was
bedridden after two weeks of chemotherapy.
DR. LOVE: Hmm. What were you
thinking at that point?
DR VENOOK: Well, of course, we were thinking
at that point that it hadn’t been the right idea to put him
on the clinical trial in the first place.
DR. LOVE: It sounds like he
kind of talked you into it.
DR VENOOK: Correct. One of the things in clinical
research is, performance status is a very important component of
your assessment of a patient, but it’s a subjective measure.
And either physicians may overestimate performance status or, more
commonly, patients who are determined to participate in studies
will rev it up for their visit and say they’re doing much
better than they really are. In this case, a week later the wife
basically called and said, “He came and saw you yesterday
and said he was doing fine, but the truth is he can’t get
out of bed.”
The real challenge is to figure out just how fit a patient is.
One of the things I often do is give the patient a few assignments
to do when I’m examining them or when they’re there
for evaluation. For example, “Could you go pick up the scans?”
And by and large, if patients aren’t up to simple tasks, then
chances are, they aren’t up to major tasks. One thing I always
do is have a patient dressed and then undress and then redress during
the same visit. If you leave the room and come back five minutes
later and the patient is still struggling to put his shorts on,
then chances are this is a poor performance status patient.
But in this patient, I think the message was he was putting on
a show for the most part. It would have been good to get corroboration
because deep down, I had concerns about his performance status.
On the other hand, he really wanted the therapy. You’re sort
of stuck between a rock and a hard place. But that’s one of
the teaching points in his case, which was, if your instinct is,
“I don’t have a good feeling about this guy,”
even if you can’t put your finger on it, chances are that’s
an instinct you need to go by.
DR. LOVE: Do you think there
was any component of guilt or self-recrimination that maybe he should
have come in earlier. It sounds like he wasn’t feeling well
for a while and that maybe he wanted to be treated aggressively
because of that?
DR VENOOK: I think that’s always a part
of the equation. I think young patients in particular feel that
they owe it to everybody around them to be fully aggressive. And
it’s, of course, the instinct of most oncologists to treat
young patients aggressively. I think the message from a case like
this is that, as we talk about the reasons not to use the aggressive
three-drug regimen, irinotecan/5-FU/leucovorin, many people go to
age as an important criterion. Age is perhaps a minor criterion,
but really the issue is performance status and the patient’s
overall condition. This patient, not surprisingly, did very poorly
with the chemotherapy, as one might have expected from his high
LDH and from his marginal performance status.
DR. LOVE: So, what did you
decide to do at that point?
DR VENOOK: We took him off study, stopped the
chemotherapy and gave him about three weeks to recover, which he
virtually did, to his baseline after about three weeks. Then, actually,
we put him on Xeloda.
DR. LOVE: How did he feel about
that idea?
DR VENOOK: He was very opposed to it. In fact,
he bargained at each visit to stay on study and to reconsider it
each consecutive visit. But at the end of a month, we just declared
that he was off study. He ultimately accepted the Xeloda, although
with hesitation. Happily, he had a major response to the Xeloda.
DR. LOVE: What dose of Xeloda
did you use?
DR VENOOK: We used 1,000 milligram per meter
squared twice a day. My own practice is not to use the 1,250 per
meter squared twice a day, which I consistently find to be more
toxic than I’m willing to accept.
DR. LOVE: Do you ever start
at a lower dose than a gram?
DR VENOOK: I have started at a lower dose than
a gram. Patients who’ve had pelvic radiation, patient’s
who’ve had chemotherapy and who are elderly and for example,
a number of patients on an Intergroup trial who received CPT-11
and oxaliplatin as a combination, who I felt were not likely to
tolerate the higher dose. So, on occasion I start it as low as 800
per meter twice a day.
DR. LOVE: Now, how many cycles
has he had and how has he tolerated the treatment in terms of side
effects?
DR VENOOK: He had six cycles. He tolerated the
first four well, and the fifth less well. He developed relatively
impressive hand-foot syndrome on the sixth cycle. He’s on
a vacation right now from his chemotherapy.
DR. LOVE: So, he had zero hand-foot,
and then all of a sudden, he had fairly bad hand-foot?
DR VENOOK: Correct. Again he had understated
his side effects all along. In retrospect, he had tingling in his
hands and feet, but never had any changes, and now he does. Of course,
the issue now is do you continue the treatment at a lower dose?
He’s petrified about taking a vacation from the treatment,
which is my instinct. This is one of the nuance issues in colon
cancer patient management. With almost any therapy, you reach a
point where you feel you have to back off for toxicity. However,
as patients have achieved responses — and in his case, a meaningful
clinical response, because he’s feeling much better —
it’s often a battle to discontinue the treatment, even if
for just a few weeks.
DR. LOVE: You mentioned the
issue of the hand-foot syndrome in this man, and there have been
reports, and there’s been some discussion here — I think
there’s an abstract right here at ASCO, looking at Celebrex.
What’s your take on that? Can you talk about that study and
what you think about it?
DR VENOOK: Well, it’s very interesting.
It’s an interesting observation. I’m always worried
about small, selective reports, so I think that’s a question
I’d like to see answered in a good randomized fashion. We’ve
not actually used Celebrex in that setting. I’ve seen Dr.
Lin’s data and I’m aware of the finding, and I’m
also aware of some preclinical models that made this not a surprising
finding. But we don’t have enough clinical experience of our
own to comment.
DR. LOVE: What’s the
last evaluation of the tumor? What did it show?
DR VENOOK: He had about an 80-percent reduction
in his hepatic metastases. His primary, of course, is still in place.
The way I ultimately sold him on stopping the Xeloda was now to
take an interval and go in and resect his primary. One of the issues
in colon cancer that has changed a bit with the availability of
new agents has been this question of what do you do for the patient
who has a synchronous presentation of their primary tumor and metastatic
disease? For many years the argument has been you resect the primary
right away and then deal with the metastatic disease, largely anticipating
problems from the primary.
While I’ve always been a proponent of that, I’ve started
edging in the other direction now, particularly in patients with
bulky disease, because I think the aggressive chemotherapy may make
a big statement in those patients. The danger of doing an operation
and losing a month of time while the patient recovers may actually
take away that window of opportunity the patient would have had.
DR. LOVE: I don’t know
of any evidence — maybe you do — that resecting a primary,
at least in colorectal cancer, is going to affect the metastatic
disease.
DR VENOOK: No, there’s no evidence that
it affects metastatic disease. But the primary concern is the need
to wait for wound healing before you can initiate systemic therapy.
The argument for taking out the primary is, if you take it out first,
you do it on your schedule, so, it’s not an emergency operation.
Let’s say you have a person with a sigmoid colon cancer that’s
nearly obstructing with metastatic disease. If you don’t take
out the primary, you run the risk of the patient presenting late
at night with an obstruction. You’ve given them aggressive
chemotherapy, they’re neutropenic and thrombocytopenic and
now you need to do a diverting colostomy because the patient is
bowel septic. Obviously, a worst case scenario, but that’s
the extreme example of what happens if you don’t take out
the primary.
But the evolution, I think, to leaving the primary in, in these
patients or many of these patients, is that your chemotherapy may
make enough of an impact that it actually is important to get it
in. In prior years, when you were dealing with 5-FU/leucovorin where
there was marginal effect on patients, it was a weak argument to
say, “Well, I want to get the chemotherapy into this patient,”
because in reality you rarely made a big impact. Now, with the different
chemotherapy choices, you can make a big impact.
DR. LOVE: But ultimately, still
the surgery for the primary tumor in this situation is for palliation.
You’re bringing up the question of whether it’s preventive
palliation where you’re going to prevent a problem. And I
would assume that that depends on where the tumor is? How big it
is? Whether it’s ulcerating? Whether it’s bleeding?
In his situation, how much concern did you have that it was going
to be a local problem?
DR VENOOK: It had already been a local problem.
He’d already seeded his liver metastases from his primary.
So, in my mind, that told me that it was a problem waiting to happen.
In general, right colon primaries are much less problematic because
the stool is liquid in the right side of the colon. Very rarely
do they present as an obstruction; they may bleed, but this patient
really hadn’t bled. In his case, because he’d already
gotten bacteremic from his primary, I viewed it as a problem waiting
to happen. And indeed, we just recolonoscoped him, and he’s
got a nasty, ugly ulcerated tumor — although not bleeding
— in his right colon by the hepatic flexure.
DR. LOVE: Interesting. Has
the picture changed on colonoscopy?
DR VENOOK: Well, the first colonoscopy was an
in-and-out rapid colonoscopy, so we were not clearly able to demonstrate
it. But by report — and they were actually different colonoscopists
— it would appear that it’s flattened and really largely
necrotic now, compared to what was a fungating mass before, as described.
But there were different colonoscopists.
DR. LOVE: Interesting. What’s
been the response of this patient in terms of his emotional state
to this experience?
DR VENOOK: Well, the good news is the patient’s
done very well. I think one of the things we don’t appreciate
is not only the benefit of a tumor regression response in the patient’s
sense of wellbeing, but also in the patient’s ability to put
things in order and to gather a perspective. So, he, of course,
is just thrilled and has now stepped back and is clearing up some
business, although very realistic about his long-term prognosis
being guarded. I think it’s unfortunate that not that many
patients have dramatic responses. The average patient in his condition
might not have enjoyed as much benefit and wouldn’t have had
the opportunity to step back and see what had happened.
I think this patient right now is reveling in the window he’s
had to revisit some issues, some personal issues, and putting more
emphasis on his kids and that kind of thing, which happens all too
late. I think the guilt in young people is rather astounding and,
of course, they have nothing to be guilty about. But it’s
very true that young patients, especially with families, somehow
blame themselves and assume they’ve done something wrong.
DR. LOVE: But he started out
at a point where he was basically bedridden with the knowledge that
he had an incurable tumor, and I guess the thought that it was possible
he was never going to feel any better than the way he felt at that
point, which sounds pretty miserable. And now, what is his general
health, his performance status?
DR VENOOK: His performance status is still not
normal, but he’s fully functional. He’s out and about
and doing his daily activities, although with a fair bit of limitation
from fatigue and some pain still. One of the interesting questions,
as oncologists, we always have to ask is, "How do you deal
with the patient who’s done very well?" Certainly, in
our initial discussion with this patient, he was fully informed
about the dismal outlook. Now one of the challenges as an oncologist
is not to burst the bubble when the patient has done incredibly
well. This is an art, and some people are better than others are
at doing it. In fact, it’s hard to know what to do. Do you
tell the patient that, “Things are going well now, but who
knows how long it will last?" Or do you just say, “Boy,
things are going well now,” and not elaborate? And a lot of
that depends on what your initial discussion with the patient was.
As a referral oncologist, I’m also often in the position
of now knowing what the patient knew at the beginning or what the
preceding story is, in which case it’s exceedingly difficult
to figure out how to capitalize on how the patient is doing today.
So, the issue with this fellow is, he’s doing very well, has
some toxicity, so, in my scheme of things, it’s “We
really achieved a lot. Let’s not lose ground here. Let’s
not be gluttons here, and accept a very good clinical result, take
out the primary and perhaps follow up with more therapy.”
I’m basing that on my recognition that the result will be
transient and we want to have the patient enjoy it for what he can.
Of course, the patient’s view might be, “Well, it’s
working, and let’s just keep at it. I want to get rid of this.”
It’s a very difficult leap for any oncologist to really explain
to any cancer patient that we’re not going to get rid of their
metastatic disease. Of course, once in a blue moon you do, but you
can’t make your treatment decisions based on the idea that
you could actually achieve that.
DR. LOVE: Now, you chose to
give him capecitabine, it sounds like particularly because of his
poor performance status. Is that your general approach to the patient
with metastatic colorectal cancer who has poor performance status?
DR VENOOK: It is. I think the hardest decisions
we had to make without data were how to use the more aggressive
therapies. Originally, when irinotecan/5-FU/leucovorin became available,
most of us made the assumption that you throw the book at the sickest
patients. These are the patients where you need to make a difference.
I think to the surprise of many, it turns out that the sickest patients
are not those who get the benefit. So, in our practice, probably
a quarter of all patients are not candidates for the aggressive,
up-front therapy, in which case I would use capecitabine as a very
excellent alternative.
Occasionally, this patient is an example where you would ask the
question, "Could we go back to the aggressive therapy or, in
other cases, start with capecitabine and then go to a more aggressive
combination?" Now, there is, of course, no evidence that you
will benefit patients by doing that, although it’s very tempting
to get another active agent with a different mechanism of action
into that patient. So, in this fellow, after his operation, if all
goes well, the debate we’ll have is whether to go to irinotecan-based
chemotherapy or continue with capecitabine. He obviously had horrendous
toxicity to irinotecan the first time around. There is no guarantee
he wouldn’t have that toxicity again, although his performance
status has improved to the point where I think there’s a reasonable
chance that he would tolerate it pretty well. Now, it’s a
different question, what he’ll be willing to do, and I don’t
know. We’ll have to see how he does after his operation.
DR. LOVE: In a way it’s
almost ironic that you chose Xeloda because of the fact that he
had such a poor performance status, and yet he had great antitumor
response. Sometimes I think we equate toxicity to antitumor effect,
and that’s not always the case. In breast cancer, a great
example is hormonal therapy. Very non-toxic therapy, and yet extremely
effective in the right patient.
DR VENOOK: Well that’s exactly true. There
is no linear relationship between the damage you do to a patient
and the damage you do to the patient’s cancer. Again, part
of our decision-making, has got to be based on performance status.
It may turn out when we’re smart enough, that we’d realize
that the same patient with a poor performance status, when we analyze
that patient’s tumors, the tumors may very well have told
us the same thing, that this patient should be treated with capecitabine
rather than irinotecan. So, they may not be mutually exclusive.
It may just be that performance status is a general way of assessing
tumor biology, which, after all, is a large part of what we do.
DR. LOVE: That’s interesting.
What do you use, other than performance status, to try to predict
toxicity to irinotecan?
DR VENOOK: That’s the main issue. Certainly,
patients who’ve had prior radiation, we anticipate will have
more toxicity to irinotecan. We’re concerned, although not
clearly based on data, that patients who have had their right colon
resected may have more toxicity, the idea being that irinotecan
is a small-bowel diarrhea or at least a component of it is small-bowel
driven. If you do a right hemicolectomy, you take out the ileocecal
valve, so the flow of diarrheal stool into the colon is greater.
So, there’s more liquid stool without a stop mechanism in
the valve at the ileocecum. So, we always worry about that, although
there’s actually a paucity of data confirming that. Anecdotally,
that’s been our assessment.
Again, in our hands, it’s mostly poor performance status,
high LDH as the dominant factors. Age certainly comes into play,
although it’s not as simple as saying, “Well, this is
a 76-year-old, ergo this is too toxic.” Of course, it’s
their physiologic age that you try to calculate. Again, if they’ve
had a right colon, we’re wary of more toxicity. There are
other people who talk about total colectomy patients. Certainly,
we have a few of those, mostly patients with polyposis, for example,
or patients with ulcerative colitis who’ve had a total bowel
resected. There’s some people who believe their diarrhea may
be greater and irinotecan not as good a choice, although that’s
a small subset of patients. I’m not sure that we can conclude
that.
The problem, of course, is that performance status is inevitably
a subjective measure. We right now are relatively crude with a zero,
one, two or performance status of 60, 70, 80, 90. It’s interesting
to talk to fellows and ask them to rate a performance status and
see how far off they are. Performance status is a very inaccurate
measurement anyway.
We had a debate at our institution not long ago, a colon cancer
patient who had had polio since the 1950s, was disabled, wheelchair
bound because of polio, but was, the best I could tell, totally
asymptomatic from their metastatic colon cancer. Yet, is this patient
a performance status of 60 or 100? Because the performance status
really should reflect the tumor-associated symptoms not the patient’s
overall wellbeing. But as patients get older or with comorbidities,
it’s a terribly subjective measure. One of the areas where
we need to make progress in oncology, especially GI cancer and colon
cancer, where many patients have trouble with appetite, with bowel
function, we really need to have a better way of assessing their
performance status than, “Can you tie your shoes? Can you
go to the grocery store,” which is what we do now.
DR. LOVE: What happened with
this patient’s CEA tumor markers?
DR VENOOK: CEA was never elevated so it turned
out. Or it was elevated minimally, to 10 or 11. It came down, but
you might have expected this to be a patient with a CEA in the thousands,
but this patient happened to have a very low CEA.
DR. LOVE: Now, for this case,
as well as basically any case of colorectal cancer from this day
on, we have to bring up the issue of what happened at ASCO, which
was the presentation by Richard Goldberg of the Intergroup study.
Can you talk a little bit about what your take is on that study
and what you think it’s going to mean over the next couple
of years, to both clinical research as well as patient care?
DR VENOOK: It’s hard to know what to do
with preliminary data. A lot of this was actuarial survival, because
many events hadn’t happened. This is a first look at a data
set. I think there are some issues of how time to progression and
time to failure were presented. It’s all the classic caveats
of not making changes in behavior based on abstracts, even if very
reputable people who have every intention of presenting the data
accurately do them.
What I expect this will mean is this will give added incentive
to the FDA to approve oxaliplatin. This study raised other issues
— the issue of how best to give 5-FU/leucovorin. One of the
distinctions in the treatment arms is the 48-hour infusion of 5-FU
with oxaliplatin versus the bolus treatment of 5-FU with irinotecan.
It’s certainly possible that that contributed to a difference.
So, there are many ways this data could go. For the moment, I think
we’ll wait for the dust to settle. Oxaliplatin presumably
will be approved, and then we’ll have the very pleasant dilemma
of figuring out how to integrate all of these therapies.
DR. LOVE: What about the issue
of Xeloda instead of 5-FU infusion combined with oxaliplatin, and
where do you see that heading?
DR VENOOK: Well, there’s a lot of data,
Phase II data, that looks at oxaliplatin and capecitabine. The data,
again, not randomized but large Phase II studies, largely in Europe,
really leave very little reason to believe that they’re not
at least equivalent to 5-FU infusional strategies. They’ve
not been compared head-to-head, but certainly appear equivalent.
I believe it’s quite possible that, as oxaliplatin gains use,
given the fact that it appears to be most effective and it’s
most well studied with infusional 5-FU regimens, it’s not
a leap of faith to use Xeloda with oxaliplatin, as opposed to the
48-hour infusion of 5-FU. Again, this may be tested at some point.
It may not be.
One of the pleasant dilemmas in colon cancer is not only do we
have now three different therapies we can mix and match, but we
have maybe bigger questions we can ask as well — How to integrate
angiogenesis inhibitors or growth factor inhibitors? And so exactly
what studies we do? Do we do a study that looks at oxaliplatin/capecitabine
versus oxaliplatin/5-FU/leucovorin? Or do we do a study that looks
at the addition of a new agent that might improve upon both? So
for those reasons, I think it’s hard to know from a regulatory
perspective where capecitabine fits, but from a practical perspective,
it’s hard to see why it wouldn’t be incorporated into
these regimens.
Now, there’s much less data with irinotecan and capecitabine.
There’s still inadequate data with capecitabine and radiation
in combination, or in addition to oxaliplatin or CPT-11. I think
in those areas, plenty more work needs to be done. But frankly,
I think there’s a wealth of European data that would suggest
oxaliplatin and capecitabine is a perfectly reasonable combination,
as would oxaliplatin/5-FU/leucovorin with capecitabine having the
advantage of its oral delivery and some other theoretical reasons
why it may be superior to 5-FU.
DR. LOVE: Assuming oxaliplatin
had been available for this patient that you presented at that exact
point in time, do you think that would have changed your approach?
DR VENOOK: That’s a very good question.
One of the things that I don’t think we know well, is what
subsets of patients are poor candidates for oxaliplatin. Now, what
literature exists might lead you to believe that no patient’s
a poor candidate for oxaliplatin, other than those with baseline
neuropathies. Remember that oxaliplatin isn’t without side
effects. In the study, more than half of all patients stopped the
oxaliplatin because of neuropathy. And it’s a very uncomfortable
paresthesias and dysesthesias – this stocking-glove neuropathy.
I think the data from Europe suggests that every patient could get
oxaliplatin. In truth, this patient I presented today might have
been a better candidate for oxaliplatin/5-FU/leucovorin than for
irinotecan/5-FU/leucovorin, if you believe the data that suggests
that poor performance status patients aren’t poor candidates
for oxaliplatin.
DR. LOVE: Again, if you had
taken that route, would you use infusional 5-FU or Xeloda in this
patient?
DR VENOOK: That’s a very good question.
At our institution we’re perfectly comfortable using infusional
5-FU. We do it all the time in studies, and we’ve done a number
of oxaliplatin studies. So, we would have done it by convention.
I think many centers, many oncologists, are not very interested
in the hassle factor of the 48-hour infusion visits. Certainly,
there’s a convenience factor for the patient. If you give
oxaliplatin/capecitabine, they are there day one and may not need
to come back for two weeks. If you give oxaliplatin/5-FU/leucovorin,
as described and as done in that study, they need to be there for
three consecutive days.
DR. LOVE: And they need some
type of port or access.
DR VENOOK: That’s right, they need an access
device and a pump.
DR. LOVE: What do you see as
the implications for this study in terms of design of trials in
the adjuvant setting?
DR VENOOK: Well, our paradigm for development
of therapies in the adjuvant setting has been, if it works in metastatic
disease, put it in the adjuvant setting. Now, an oxaliplatin regimen
has been tested in the adjuvant setting, although not the same one.
I believe this data makes it plausible that an adjuvant study, might
look at oxaliplatin/5-FU/leucovorin as one arm.
Now, what do you compare it to? Well, we’ve completed a study
looking at irinotecan/5-FU/leucovorin compared to 5-FU/leucovorin.
We know that the irinotecan/5-FU/leucovorin arm was unacceptably
toxic, a 2.5 percent death rate, and we don’t know if there
was as survival advantage. So, while I think oxaliplatin is a perfectly
valid arm for an adjuvant study, I’m not sure what the control
arm would be.
I think there’s another issue with oxaliplatin, and while
it’s natural to look at it in the adjuvant setting, one of
the things that you can’t be too happy about with an adjuvant
therapy are long-term toxicities. If you look at the data 50-some
percent of patients had significant neuropathy. Now, neuropathy
with oxaliplatin may be dose-related, or cumulative dose-related,
or may not. But one of the issues we need from the study that was
recently done in oxaliplatin is what’s the long-term neuropathy
for patients? So, if you take node-positive colon cancer patients,
50 percent of whom are already cured, and maybe, if you can get
up to 70 percent, that’s great, with oxaliplatin. But you’ve
still treated 50 patients out of your 100 who didn’t need
the therapy, and if you’re going to cause a substantial neuropathy
that may affect them for the rest of their lives, this might be
relevant. I think one of the important issues in drug development, and we
do take things from the metastatic setting to the adjuvant setting.
However, of course, we’ll accept much less toxicity in the
adjuvant setting than we will in the metastatic setting, unless
we get a lot of benefit for it. So I think the studies need to be
done, but I’m not so excited that oxaliplatin’s going
to be a slam-dunk the adjuvant setting. If you’re left with
a lot of cancer survivors who can’t button their shirts or
can’t tie their shoelaces because of a substantial neuropathy,
you will have made a tradeoff.
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